Tramadol in maintenance of opioids

Substance Use & Misuse

ISSN: 1082-6084 (Print) 1532-2491 (Online) Journal homepage: http://www.tandfonline.com/loi/isum20

Can Tramadol be Used for Maintenance Treatment of Opioid Dependence?

Siddharth Sarkar, Rakesh Lal, Mohit Varshney, Saurabh Kumar & Yatan Pal Singh Balhara

To cite this article: Siddharth Sarkar, Rakesh Lal, Mohit Varshney, Saurabh Kumar & Yatan Pal Singh Balhara (2018): Can Tramadol be Used for Maintenance Treatment of Opioid Dependence?, Substance Use & Misuse, DOI: 10.1080/10826084.2018.1521427

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SUBSTANCE USE & MISUSE

https://doi.org/10.1080/10826084.2018.1521427

Can Tramadol be Used for Maintenance Treatment of Opioid Dependence?

Siddharth Sarkar , Rakesh Lal, Mohit Varshney, Saurabh Kumar, and Yatan Pal Singh Balhara

National Drug Dependence Treatment Centre, All India Institute of Medical Sciences, New Delhi, India

ABSTRACT

Background: Certain limitations of the existing opioid substitution therapies necessitate exploration of other options for maintenance of patients with opioid dependence. This study aimed to present the experience of use of tramadol for long-term treatment of patients with opioid dependence. Methods: This was a cross-sectional interview-based observational study conducted in Uttar Pradesh state in India. Patients with opioid dependence who received oral tramadol treatment for a period of more than 6 months were recruited. Outcome was assessed in terms of self-reported abstinence on tramadol. Results: A total of 102 participants were recruited in the study, with a mean age of 41.3 years. All the participants were males. Abstinence to extraneous opioids was reported by 58.8% of the sample, and the median dose of tramadol at which abstinence was achieved was 350mg/d. Those who reported to be taking natural opioids (raw opium or poppy husk) at the time of seeking treatment had higher rates of achieving abstinence. Conclusions: Tramadol may be a possible option for the maintenance treatment among some opioid-dependent individuals. Further studies are required to establish its efficacy vis-a-vis other medications used in opioid substitution treatment.

KEYWORDS

Harm reduction; maintenance treatment; opioid dependence; opium; tramadol

Introduction

Opioids continue to be the main problem drug worldwide, accounting for some 60% of treatment demand in Asia and in Europe (UNODC, 2015). More than half of the world’s opioid using population lives in Asia, with the highest levels of abuse occurring along the main drug trafficking routes out of Afghanistan (United Nations, 2015). Opioid abuse continues to rise in Asia, mainly among countries close to Afghanistan including India, Bangladesh, Nepal, Bhutan Pakistan, the Central Asian countries and the Russian Federation (Ghotbi & Tsukatani, 2007). Thus, opioid dependence is likely to be a major clinical and public health challenge in the region, necessitating expansion of treatment services and therapeutic options.

One of the most efficacious and cost-effective treatment for long-term management of opioid dependence is opioid substitution therapy (OST). Methadone and buprenorphine are the commonly used OST medications which have been in use for decades now (Darke & Farrell, 2016; Dennis et al., 2014; Kermode, Crofts, Kumar, & Dorabjee, 2011; Lawrinson et al., 2008; Zippel-Schultz et al., 2016).

Many patients move between these two treatments over the course of time, depending on their needs in terms of dispensing (Gutwinski, Bald, Gallinat, Heinz, & Bermpohl, 2014; Ling, Rawson, & Compton, 1994; Prakash &Balhara, 2016; Threlkeld, Parran, Adelman, Grey, & Yu, 2006). Despite the scale-up of OST services in certain areas like India and South Asia, the overall coverage of OST remains low; and various barriers exist between service providers and recipients (Rao, Agrawal, Kishore, & Ambekar, 2013). One of these barriers reported by the recipients is the dispensing pattern and the need to come frequently to the centers for obtaining the mediation (Oliva, Maisel, Gordon, & Harris, 2011; Richardson, Wood, Montaner, & Kerr, 2012; Sto€ver, 2011). Restrictive policies in supply and clinical use of these medications deter away physicians from recommending OST as an option. Moreover, lack of therapeutic options has also been suggested as a structural barrier for treatment (Sharma & Chatterjee, 2012).

Hence, there is a need to explore other options for long-term management of opioid dependence. Previously, several options have been tried for opioid substitution. These include medications like slow

CONTACT Siddharth Sarkar sidsarkar22@gmail.com Department of Psychiatry and NDDTC, All India Institute of Medical Sciences, Room No 4096, Teaching Block, New Delhi 110029, India.

” 2018 Taylor & Francis Group, LLC

2 S. SARKAR ET AL.

release oral morphine and codeine, though the litera- ture is limited (Ferri, Minozzi, Amato, Bo, & Davoli, 2013; Krausz, Verthein, Degkwitz, Haasen, & Raschke, 1998). Tramadol has been found to have good efficacy in the treatment of opioid withdrawals, particularly of mild to moderate severity (Lofwall et al., 2013; Lofwall, Walsh, Bigelow, & Strain, 2007; Mandal & Prakash, 2015). Anecdotal evidence exists suggesting that tramadol can be used for the long-term treatment of opioid dependence in selected individuals (Gyawali & Sarkar, 2016; Tewari & Sarkar, 2017). Low abuse potential and safety in moderate doses makes it a possible candidate for long-term treatment of opioid dependence (Babalonis, Lofwall, Nuzzo, Siegel, & Walsh, 2013; Boostani & Derakhshan, 2012; Cicero et al., 2005 Threlkeld et al., 2006). We have previously published a retrospective chart review study of patients with opioid dependence who had been maintained on tramadol (Sarkar, Lal, Varshney, & Balhara, 2017). We present here our prospective inter- view-based study of patients with opioid dependence who received treatment with tramadol for substantial periods of time.

Methods

Study setting and participants

This descriptive observational self-report based study was conducted at the National Drug Dependence Treatment Centre (NDDTC); a tertiary care center for the treatment of substance use disorders in northern India in Uttar Pradesh state. The center is a public- funded institution and receives both referred and non-referred patients. The center receives a substantial proportion of patients with opioid dependence who have been taking either heroin natural opioids or prescription opioids. Natural opioids include raw opium or poppy husk, and these have been in use in parts of South Asia for a long time (Ganguly, Sharma, & Krishnamachari, 2006). Natural opioid users constitute about one-fifth of the treatment-seeking opioid-dependent individuals in the region (Basu et al., 2012). A recent population survey suggests that natural opioids are probably the second most common type of opioids being abused in the region (Ambekar et al., 2015).

The patients seeking treatment at the NDDTC are diagnosed using ICD 10 classification system by trained psychiatrists. Treatment is started after intake interview based upon clinical needs. The patients with opioid dependence are typically prescribed buprenorphine for opioid agonist maintenance or for

withdrawal management. However, considering the risk of diversion, patients generally receive daily supervised dosing from the center in the initial period. A subset of patients who are unable to take supervised buprenorphine are offered oral tramadol for managing withdrawals on out-patient basis, with the aim of tapering down the dose (i.e. detoxifying) over the course of a few weeks. Tramadol is prescribed gener- ally for a period of 2–3 weeks and is dispensed from the center. Some of the patients who are prescribed tramadol seem to experience reduction of withdrawal symptoms. Yet, many find it difficult to taper off the doses of tramadol over the course of follow-up and hence, continue to take it for considerable periods of time in order to abstain from illicit opioid use. This study aimed to evaluate such patients who received tramadol without completely tapering it off over a course of 6 months. The inclusion criteria were: patients with a diagnosis of opioid dependence according to ICD 10 criteria (World Health Organization, 1992), aged 18 and above, and having received tramadol over a period of more than 6 months (verified from the prescriptions). Those who refused informed consent or those who had significant withdrawal symptoms were excluded from the study.

Study procedure

This was a cross-sectional observational interview- based study. The participants who fulfilled the inclu- sion and exclusion criteria were evaluated with the help of a semi-structured questionnaire by one of the investigators. The questionnaire included demographic details, substance use details, information related to tramadol use, any adverse events, and their preferen- ces toward tramadol. The duration of use of tramadol was also recorded. The outcomes of the patients in terms of attainment of cessation of other opioid use were also ascertained. Abstinence status was assessed with self-report of the patient and corroboration with family members when available. Abstinence was oper- ationalized as cessation of extraneous/illicit opioid use for a period of at least 1 month. Follow-up adherence was computed as a percentage by dividing the number of times patients actually turned up for follow-up or prescription refill by the number of times they were asked to during the course of treatment. Additionally, the patients were asked about diversion of prescribed tramadol and the maximal dose used. The question- naire was clinician-administered and was developed for this study. Data collection lasted from January 2017 to May 2017, and the target sample size was

about one hundred patients based on exploratory nature of the study. The study has institutional ethics committee approval (IEC/521/10/2016).

Statistical analysis

The analysis was primarily descriptive in nature and was conducted using SPSS version 21 (IBM Corp, Armonk, NY). Mean, standard deviation, median, range, frequency, and percentages were used to represent the data. Inferential statistics was used to assess relationship between the variables of interest. Student’s t test, Mann–Whitney U test and v2 test were used as applicable. A p value of less than .05 was considered significant for the tests of significance. Missing value imputation was not performed for this study.

Results

A total of 102 participants were enrolled in the study. The demographic and clinical characteristics of the sample are shown in Table 1. All the participants in the study comprised of males. The mean age of the

Table 1. Demographic characteristics of the sample.

Mean (SD) or

sample was 41.3 years (range of 19–70 years). A majority of the participants were married, were educated up to the 10th grade, lived in an extended or a joint family, and were from rural background. The median duration of opioid use was 12 years with a range from 1 to 45 years. A substantial proportion of participants in the study reported to be taking natural opioids (poppy husk or raw opium) prior to seeking treatment at the center; followed by heroin users. The most common diagnosis related to another substance of user pertained to tobacco, followed by cannabis, alcohol, and benzodiazepines.

The reason of initiation of tramadol was reported to be logistic problems in coming daily for buprenor- phine dispensing in all the patients. The tramadol treatment-related characteristics of the sample are shown in Table 2. The table also shows the same characteristics of patients who were users of natural opioids. The median dose of tramadol initiation and the most common dose of prescribed tramadol was 300mg/d. The median maximum dose during the course of treatment was reported to be 350 mg/d. The median duration of tramadol treatment at the center was 8 months. The median follow-up adherence was 80%. About 60% of the patients admitted to have taken excess doses of tramadol than prescribed.

Sixty out of a total of 102 participants (58.8% of the sample) achieved abstinence to extraneous opioids at least for a period of one month. Among the rest 42 participants, 39 reported reduction in the use of extraneous opioids. Taken together, 99 patients (about 97.1% of the sample) were deemed to have some benefit with oral tramadol. Further exploratory analysis was done to find relationship of becoming abstinent with other clinical variables. It was seen that the rates of achieving abstinence were higher among users of natural opioids compared to others (81.6% versus 37.7%, v2 1⁄4 20.255, d.f. 1⁄4 1, p<.001). Also, older patients (mean age 45.1 versus 35.9 years, t 1⁄4 3.385, p 1⁄4 .001), those with long duration of opioid use (mean 17.8 versus 11.7 years, U1⁄4839.0, p1⁄4.004) and those who had a better follow-up adherence (mean 80.5% versus 60.0%, U 1⁄4 475.5, p < .001) seemed to have higher rates of achieving abstinence. The dose of tramadol being prescribed or the duration of treatment with tramadol did not have a relationship with the achievement of abstinence.

Among the 60 participants who had achieved abstinence, 31 had relapsed to extraneous opioid use (a little over 50%). The type of opioids being used, age of the participant, and dose of tramadol did not have a relationship with the propensity of relapse.

Socio-demographic variable

Age in years Gender

Male Marital status

Currently married

Currently not married Educational status

Not formally educated Educated up to 10th grade Educated above 10th grade

Living arrangement Alone

Nuclear family

Extended/joint family Religion

Hindu Sikh Islam

Clinical parameters

Diagnosis with relation to opioid use

Dependence (ICD 10)

Duration of opioid use in years Type of opioids being used before

seeking treatment here Natural opioids

Heroin

Prescription

Mixed

Other diagnoses (ICD 10)

Tobacco dependence Cannabis dependence Alcohol dependence Benzodiazepine

frequency (percentage) 41.3 (14.2)

102 (100%)

87 (85.3%) 15 (14.7%)

28 (27.5%) 67 (65.6%) 7 (6.9%)

4 (3.9%) 31 (30.4%) 67 (65.7%)

59 (57.8%) 19 (18.6%) 24 (23.5%)

102 (100%) 12 (1–45)

49 (48.0%) 31 (30.4%) 3 (2.9%) 19 (18.6%)

92 (90.2%) 10 (9.8%) 7 (6.9%) 5 (4.9%)

Health Related

SUBSTANCE USE & MISUSE 3

ICD10: International Classification of Diseases and Conditions, 10th Edition.

4 S. SARKAR ET AL.

Table 2. Treatment-related characteristics of the sample. Variable

Dose of tramadol at initiation

Maximum dose of tramadol prescribed

Most common dose of tramadol prescribed

Duration of tramadol treatment in months

Follow-up adherence in percent

Did the patient take excess doses than prescribed Maximum doses of tramadol taken by patient

Side effects experienced with maximum doses Abstinence achieved on prescribed tramadol

Dose at which abstinence achieved

Duration of abstinence if abstinence achieved (months) Reduction of illicit opioids if abstinence not achieved Relapse to extraneous opioids after achieving abstinence Reasons of relapse

Withdrawals

Peer pressure

Medication discontinuation Craving

Others†

Adverse events with tramadol Seizures

Increased use of other substances after tramadol initiation

Shown as frequency (percentage) or median (range), doses mentioned in mg/day.

†Others included negative mood, pain, work pressure, and multiple factors for 1 patient each.

Table 3. Treatment-related characteristics of the sample. Variable

Did the patient ever try buprenorphine

Preferred opioid among buprenorphine or tramadol for those who have used both

Buprenorphine

Tramadol

Procured tramadol from chemist

Procured tramadol from others (but not chemists) Gave own supply of tramadol to others

Reasons of giving own supply as mentioned by patients† To help other patients in need

To exchange for buprenorphine

To get money

To show effect to other substance users Shown as frequency (percentage).

†Information available from 8 to 4 patients.

However, longer duration of opioid use was associated with increased chances of relapse (mean 20.9 versus 15.5 years, U 1⁄4 309, p 1⁄4 .034) and longer duration of tramadol use was associated with greater chances of relapse (11.4 versus 8.2 months, U 1⁄4 267, p 1⁄4 .006). As depicted in Table 2, only one patient reported an adverse event while using prescribed dose of tramadol in the form of a seizure.

Some of the other treatment-related characteristics of the sample are shown in Table 3. More than half of the patients who were on tramadol had tried buprenorphine, and an overwhelming majority of them preferred buprenorphine to tramadol. Yet, they were constrained for prescription of tramadol. A minority also reported procuring tramadol from a chemist and other sources. The median going rate of procuring tramadol from others was Indian Rupees 5 per tablet, or 50 per strip (a strip of 10 tablets costing roughly less than US$1). Less than a tenth of the

Entire sample (n 1⁄4 102) 58 (56.9%)

49 (84.5%) 9 (15.5%) 11 (10.8%) 20 (19.6%)

9 (8.8%)

4 (50.0%) 2 (25.0%) 1 (12.5%) 1 (12.5%)

Entire sample (n 1⁄4 102) 300 (200–400)

350 (200–450) 300 (200–450) 8 (6–30)

80 (25–100)

60 (58.8%) 400 (200–1000)

9 (15.0%) 60 (58.8%)

350 (250–400) 6 (1–18)

39 (92.9%) 31 (51.7%)

15 (48.4%) 5 (16.1%) 4 (12.9%) 3 (9.7%) 4 (12.9%)

1 (1.0%) 3 (2.9%)

Natural opioid users (n 1⁄4 49) 300 (200–400)

350 (250–450) 300 (200–400) 9 (6–30)

81.5 (50–100) 26 (53.1%) 400 (250–600) 4 (8.2%)

40 (81.6%)

300 (250–400) 6 (1–18)

9 (100%) 22 (44.9%)

12 (54.5%) 5 (22.7%) 1 (4.5%) 2 (9.1%) 2 (9.1%)

0 (0%) 0 (0%)

Natural opioid users (n 1⁄4 49) 20 (40.8%)

15 (75%) 5 (25%) 5 (10.2%) 9 (18.4%) 5 (10.2%)

3 (75%) 1 (25%) –

sample reported that they gave their own supply of tramadol to others, primarily to “help” other patients in need who could not procure tramadol.

Discussion

This study indicates towards some support that trama- dol may have a place in the long-term management of opioid dependence, apart from its use for manage- ment of acute withdrawal. Recommendation for its use for long-term management has been made based upon the low abuse liability of this medication (Das, Jain, Dhawan, & Kaur, 2016; Mandal & Prakash, 2015). Moreover, it fits in with three of the four basic assumptions of harm-reduction approach: reduction of harms, client needs’ first and low threshold services (Marlatt, 1996).

The goals of pharmacotherapy in long-term management include prevention or reduction of

withdrawal symptoms, prevention, or reduction of drug craving, prevention of relapse to addictive drug use, and restoration toward normalcy of physiological function disrupted by drug abuse (Kreek, 1992; Salsitz & Wiegand, 2016). The pharmacological treatment is contextualized in the service delivery characteristics including access to care for medical, behavioral, and rehabilitation related issues. In this study, approxi- mately 60% opioid-dependent individuals achieved abstinence. The proportion increased to more than 80% in patients using natural opioids. Moreover, less than ten percent relapsed to their primary opioid of abuse due to craving; indicating significant reduction in this parameter while on tramadol. Additionally, in the natural opioid group, no patient increased other substance of abuse while on treatment. This may sug- gest restoration of physiological function disrupted by use of natural opioids prior to initiation of tramadol.

In central and south Asia, natural opioids have been abused for centuries (Kulsudjarit, 2004); and constitute up to 16% of treatment seekers in India (Balhara, Mishra, Sethi, & Ray, 2013). A pro-heroin effect has been described, i.e. increased propensity of using heroin with decreased availability of natural opioids in traditionally opium using population (Ganguly et al., 2006; Westermeyer, 1976). This con- stitutes significant potential burden on the health-care system, despite the lesser harms perceived for natural opioids compared to other illicit drugs (Sarkar, Balachander & Basu, 2014). Thus, natural opioids probably represent a sub-group whose treatment needs may be different from other opioids. Tramadol seems to be a possible therapeutic option for mainten- ance treatment in natural opioid users. It seems to fulfill five out of eight requirements for choosing long-term agents for pharmacotherapy; i.e. being an agonist, pharmacological stability, dose-response, and reduction in craving and salience (Darke & Farrell, 2016; Kreek, Borg, Ducat & Ray, 2010).

However, an equally essential requirement for long- term agent is safety, in terms of toxicity, and cognitive and psychiatric sequelae following administration. The neurotoxicity of tramadol commonly manifests as gen- eralized tonic-clonic seizures and has been reported to be more common in individuals consuming alcohol and other illicit drugs concomitantly (Boostani & Derakhshan, 2012). Available literature reports a lower risk of seizures and other side effects when taken in moderate doses (up to 400mg) (Boostani & Derakhshan, 2012; Marquardt, Alsop& Albertson, 2005). Furthermore, tramadol as a suitable long-term agent does not meet the criteria of having single daily

administration and ability to block the effect of exogenously taken opioids (Driessen, Reimann, & Giertz, 1993). Another important aspect of using tramadol for long-term is the propensity of diversion. The diversion is quite linked to policies of the treatment facility and the dispensing regimen. We do probably need to acknowledge that diversion did occur among the participants. However, patients preferred buprenoprhine over tramadol when they had access to both, suggesting that buprenorphine should probably be more tightly regulated.

Relapse to illicit opioids occurred in a substantial proportion of individuals who attained abstinence in this study. High relapse rates have been found in other naturalistic studies of buprenorphine or metha- done based OST (Wittchen et al., 2008). Yet, efforts are required, especially in the form of concerted care including psychosocial rehabilitation, to reduce these relapse rates. A unique feature of this sample was that it comprised of males exclusively. This could be attributed to a very low proportion of females accessing treatment services in this part of the world, as well as treatment-related barriers that may lead to discontinuation of treatment of women who eventually seek care (Lal, Deb & Kedia, 2015).

Overall, the results of our study suggest that when used in moderate dosages (300–400 mg) tramadol appears to be a good alternative in the medium and long-term management of a sub-population of opioid- dependent individuals. When looked from a harm- reduction perspective in the sub-population, it appears to be a viable alternative for resource-limited settings and warrants further research. Also, the restrictions on prescription and sale of tramadol are lesser than that of buprenorphine and methadone, making it eas- ier to procure and dispense in the clinical setting for therapeutic purposes by a wider range of practitioners (Chawla et al., 2013; Stoops et al., 2012).

The study, however, has its own limitations in terms of an observational design and included only those individuals who completed 6 months of treatment with tramadol. This could have biased the findings as it would omit results of patients where tra- madol might not have produced desired results. Also, the information about abstinence was based upon self- report without corroboration with biological samples. The amount of opioids being used at the time of initiation of the treatment was not accounted for (given the different forms of opioids being used), though the amount being consumed might have influenced the outcome. The study was conducted in a single center in a specific geographical location and

SUBSTANCE USE & MISUSE 5

6 S. SARKAR ET AL.

the sample comprised only of males. More import- antly, the access to other opioid substitution treatment might be different in other centers and health systems, and hence the necessity of using tramadol as an option would be perceived differently. Hence, general- ization of the study should be made with caution.

To conclude, tramadol seems to be an option for the maintenance treatment of opioid dependence. Seemingly patients who have been using natural opioids seem to do better on this medication as compared to others. Further research is required to strengthen the evidence for tramadol as a maintenance agent for opioid-dependent individuals, possibly using objective measure of drug use like urine screening, and subsequently a double-blind randomized controlled efficacy trial with active comparator. The utility and acceptability of this medication in the opi- oid-dependent individuals needs further exploration. Also, the safety profile needs to be assessed through long-term follow-up. Nevertheless cross-sectional and cohort-based information from the patients who are maintained on this medication may also provide valuable insights about utility of this medication as a maintenance agent. The collected evidence can eventually guide policy decisions for implementing judicious use of tramadol in resource-limited settings, or in circumstances where regulatory frameworks restrict the use of other opioid agonists.

Declaration of interest

The authors declare that they have no conflict of interest. The authors alone are responsible for the content and writing of the article.

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ORCID

Siddharth Sarkar

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